Abstract

Allogeneic hematopoietic cell transplantation (alloHCT) is limited by acute graft-versus-host disease (GvHD) which occurs in 30-40 % of patients. Despite numerous clinical studies, the standard immunosuppressive regimens for prevention of acute GvHD have changed little in the last two decades. A better understanding of the pathophysiology of GvHD may help to improve the outcome after alloHCT.

Acute GvHD is mediated by donor T cells that are activated by recipient antigen-presenting cells (APCs). Since microRNA-155 (miR-155) was shown to regulate the activation of different innate immune cell subsets, we aimed to determine its function for APCs during an allogeneic immune response.

We observed upregulation of miR-155 in recipient APCs residing in secondary lymphoid organs and in the intestinal tract when GvHD developed. By using gene targeted mice, we observed that miR-155 deficiency of the recipient led to improved survival (p=0.0011), lower GvHD histopathology scores (small bowel: p=0.0003, large bowel: p=0.0209, liver: p=0.0035) and reduced serum levels of proinflammatory cytokines (IFNγ: p=0.0305, IL-12: p=0.0274, MCP-1: p=0.0016). Using miR-155-/- bone marrow chimeric mice lacking miR-155 in the hematopoietic system and adoptive transfer of miR-155+/+ versus miR-155-/- APCs, we determined that this phenotype was dependent on miR-155 deficiency in the APC compartment. Mechanistically, miR-155-/- APCs showed reduced ERK phosphorylation in response to lipopolysaccharides (LPS) and adenosine-5'-triphosphate (ATP) as compared to miR-155+/+ APCs. Cleaved caspase-1, the indicator of an active NLRP3 inflammasome, was also reduced in miR-155-/- APCs. Conversely, suppressor of cytokine signaling 1 (SOCS1), a known target of miR-155, was increased in miR-155-/- APCs as compared to miR-155+/+ APCs. SOCS1 leads to proteasomal degradation of the p65 subunit of NF-κB and thereby may interfere with NLRP3 inflammasome activation.

Overall, our data indicate that miR-155 is required in the recipient APC compartment for NLRP3 inflammasome activation in response to LPS and ATP. These findings could help to reduce tissue damage related proinflammatory effects induced by LPS and ATP which activate the intestinal immune system following cytotoxic therapy by antagonizing miR-155 function with antagomir treatment.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.